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2 Selected Applications of Spirocycles in Medicinal Chemistry
Matthias Baud
School of Chemistry and Institute for Life Sciences, University of Southampton, Southampton, UK
2.1 Introduction
Spiro compounds contain two rings, connected by a single sp3 hybridized quaternary center, the “spiroatom” [1]. The latter is often a carbon, although a number of quaternary N‐spiro ammoniums have also been reported. Trospium chloride (1) (Table 2.1) is a good example, and its spiro ammonium motif can be readily prepared by double N‐alkylation of endo‐nortropine [3]. Spirocyclic systems are found in a wide range of natural products [4], including spiro‐ketals [5, 6], lactones [7], lactams [8, 9], and oxindoles [10–12]. An early and illustrative example of spirocyclic natural product which has attracted the attention of medicinal chemists is the antibiotic platensimycin (2). It is a metabolite from Streptomyces platensis which represents a structurally unusual example of bioactive molecule containing a carbaspirocyclic scaffold. Its antibiotic activity was reported by Merck in 2006, as part of a screening campaign to identify inhibitors of beta‐ketoacyl synthases I/II (FabF/B) enzymes [13]. Inhibition of FAB enzymes by platensimycin leads to impaired biosynthesis of key fatty acids required bacterial cell membrane integrity [14]. Platensimycin displays activity against a range of Gram‐positive bacteria, including strains showing resistance to other potent antibiotics such as methicillin, vancomycin, linezolid, or macrolide. Structural studies on an Escherichia coli FabF(C163Q) in complex with platensimycin highlighted important interactions underlying complex formation. The shape complementarity and conformational restriction provided by the spiro motif are important contributors to the potency of platensimycin, allowing polar interactions and hydrophobic contacts at the binding site entrance (Figure 2.1) [13]. The first total synthesis of racemic platensimycin was reported by Nicolaou on the same year (Scheme 2.1) [15], involving a key ruthenium‐catalyzed enyne cycloisomerization [16]. Since then, stereoselective syntheses of platensimycin spirocyclic core based on rhodium‐catalyzed asymmetric cycloisomerization and hypervalent iodine‐mediated de‐aromatizing cyclization [17], decarboxylative allylation [18], and intramolecular Diels–Alder [19] have been reported.
Table 2.1 Selected examples of FDA‐ approved drugs containing spirocyclic motifs.
Source: Adapted from Knox et al. [2].
| Structure | ID | Name (Trade name) | Indication |
|---|---|---|---|
|
|
1 | Trospium chloride (Flotros) | Overactive bladder |
|
|
3 | Spironolactone (Aldactone) | Heart failure, edema, hypertension |
|
|
4 | Cevimeline (Evoxac) | Dry mouth (Sjögren's Syndrome) |
|
|
5 | Griseofulvin (Crivicin) | Antifungal antibiotic for ringworm infections |
|
|
6 | Guanadrel (Hylorel) | Hypertension |
|
|
7 | Amcinonide (Cyclocort) | Inflammatory and pruritic manifestations |
|
|
8 | Ivermectin (Ascapil) | Anti‐parasitic |
|
|
9 | Fenspiride (Eurespal) | Antitussive |
|
|